Riluzole is marketed for the treatment of amyotrophic lateral sclerosis. This compound is also useful as an anticonvulsant, an anxiolytic and a hypnotic (EP50551), in the treatment of schizophrenia (EP305276), in the treatment of sleep disorders and of depression (EP305277), in the treatment of cerebrovascular disorders and as an anaesthetic (EP282971), in the treatment of spinal, cranial or cranio-spinal traumas (WO94/13288), as a radio restorative (WO94/15600), in the treatment of Parkinson's disease (WO94/15601), in the treatment of neuroAIDS (WO94/20103), and in the treatment of mitochondrial diseases (WO95/19170).
Glutamate is one of the most widespread and most important neurotransmitters of the nervous system. Its effects on the neurons are modulated by transport proteins which cause glutamate to penetrate inside cells. The molecular structure of four glutamate transporters is well known (Gegelashvili, G. and Schousboe, A., J. Pharmacol. Exp. Ther., 52: 6-15, 1997; Takahashi, M. et al., J. Exp. Biol., 200: 401-409, 1997) and a fifth transporter has been recently identified (Arriza, J. L., et al., Proc. Natl. Acad. Sci. USA, 94: 4155-4160). Methods of histological localization indicate that these transporters are not all uniformly present in the various types of cells encountered in the nervous system. Two of the first transporters identified, called GLAST (or EAAT1) and GLT-1 (or EAAT-2), are predominantly located in the glial cells. The transporter EAAC-1 (EAAT-3) is expressed by the neurons through the whole brain. The transporter EAAT-4, more recently identified, is mainly expressed by a specific type of cerebellar neurons called Purkinje cells (Nagao, S., et al., Neurosciences, 78: 929-933, 1997). The most recently identified transporter is called EAAT-5 and is found in the retina of the eye.
The Purkinje cells use gamma-aminobutyric acid (GABA) as neurotransmitter. Glutamate being a metabolic precursor of GABA (Biochemistry and the Central Nervous System, McIlwain, H. M., and Bachelard, H. S. (eds.), Churchill Livingston, London, 1971, p. 193), one of the roles of the transporter EAAT-4 would be to participate in the supply of glutamate to the cerebellar Purkinje cells in order to ensure the synthesis of their neurotransmitter. This is corroborated by recent studies which show that the loss of the transporter EAAT-4, unlike that of the transporters EAAT-1, EAAT-2 and EAAT-3, causes cerebellar dysfunction which causes ataxia-type behavioral symptoms in rodents (Maragakis, N., et al., Soc. Neurosci. Abstr., 23: 1484, 1997).